Tpl2 Ablation Leads to Hypercytokinemia and Excessive Cellular Infiltration to the Lungs During Late Stages of Influenza Infection.
Tpl2 Ablation Leads to Hypercytokinemia and Excessive Cellular Infiltration to the Lungs During Late Stages of Influenza Infection.
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DOI：
10.3389/fimmu.2021.738490
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发表时间：
2021
影响因子：
7.3
通讯作者：
Watford WT
中科院分区：
文献类型：
--
作者：
Latha K;Jamison KF;Watford WT
肿瘤进展位点2 （Tpl2）是一种丝氨酸-苏氨酸激酶，已知可促进炎症反应，以响应各种病原体相关分子模式（PAMPs），炎症细胞因子和g蛋白偶联受体，从而有助于宿主抵抗病原体。我们最近的研究表明，Tpl2-/-小鼠死于低致病性流感毒株（x31, H3N2）的感染，机制未知。在这项研究中，我们试图表征流感感染的Tpl2-/-小鼠的细胞因子和免疫细胞谱，以深入了解其宿主保护作用。尽管Tpl2-/-小鼠表现出适度的病毒控制受损，但在发病和死亡高峰当天，Tpl2-/-小鼠的肺部没有观察到病毒，这表明发病不是由于病毒的细胞病变作用，而是由于过度活跃的抗病毒免疫反应。事实上，在感染后7天（dpi），在流感感染的Tpl2-/-小鼠肺中观察到干扰素-β (IFN-β)、IFN诱导的单核细胞趋化蛋白-1 （MCP-1, CCL2）、巨噬细胞炎症蛋白1α (MIP-1α; CCL3)、MIP-1β (CCL4)、RANTES （CCL5）、IP-10 （CXCL10）和干扰素-γ (IFN-γ)水平升高。细胞因子和趋化因子的升高伴随着肺部炎症单核细胞和中性粒细胞的浸润增加。此外，我们注意到IFN-β升高与肺部CCL2、CXCL1和一氧化氮合酶（NOS2）表达升高相关，这与严重的流感感染有关。Tpl2消融局限于放射耐药细胞的骨髓嵌合体证实，Tpl2至少部分地在放射耐药细胞中起作用，以限制对病毒感染的促炎反应。总的来说，这项研究表明，Tpl2通过抑制干扰素和趋化因子的产生来缓解流感感染期间的炎症，这些干扰素和趋化因子可以促进有害的炎症单核细胞和中性粒细胞的募集。
Tumor progression locus 2 (Tpl2) is a serine-threonine kinase known to promote inflammation in response to various pathogen-associated molecular patterns (PAMPs), inflammatory cytokines and G-protein-coupled receptors and consequently aids in host resistance to pathogens. We have recently shown that Tpl2-/- mice succumb to infection with a low-pathogenicity strain of influenza (x31, H3N2) by an unknown mechanism. In this study, we sought to characterize the cytokine and immune cell profile of influenza-infected Tpl2-/- mice to gain insight into its host protective effects. Although Tpl2-/- mice display modestly impaired viral control, no virus was observed in the lungs of Tpl2-/- mice on the day of peak morbidity and mortality suggesting that morbidity is not due to virus cytopathic effects but rather to an overactive antiviral immune response. Indeed, increased levels of interferon-β (IFN-β), the IFN-inducible monocyte chemoattractant protein-1 (MCP-1, CCL2), Macrophage inflammatory protein 1 alpha (MIP-1α; CCL3), MIP-1β (CCL4), RANTES (CCL5), IP-10 (CXCL10) and Interferon-γ (IFN-γ) was observed in the lungs of influenza-infected Tpl2-/- mice at 7 days post infection (dpi). Elevated cytokine and chemokines were accompanied by increased infiltration of the lungs with inflammatory monocytes and neutrophils. Additionally, we noted that increased IFN-β correlated with increased CCL2, CXCL1 and nitric oxide synthase (NOS2) expression in the lungs, which has been associated with severe influenza infections. Bone marrow chimeras with Tpl2 ablation localized to radioresistant cells confirmed that Tpl2 functions, at least in part, within radioresistant cells to limit pro-inflammatory response to viral infection. Collectively, this study suggests that Tpl2 tempers inflammation during influenza infection by constraining the production of interferons and chemokines which are known to promote the recruitment of detrimental inflammatory monocytes and neutrophils.
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